Key Points Question Is use of glycolysis-enhancing drugs, such as terazosin, doxazosin, and alfuzosin, associated with decreased risk of Parkinson disease compared with use of tamsulosin, a drug prescribed for similar indications but which does not enhance glycolysis? Findings In this cohort study of 147 248 propensity score–matched pairs of terazosin/doxazosin/alfuzosin users and tamsulosin users from Danish nationwide health registries and the Truven Health Analytics MarketScan, the use of terazosin/doxazosin/alfuzosin was associated with a 12% to 37% decrease in Parkinson disease risk compared with use of tamsulosin. Meaning Use of terazosin/doxazosin/alfuzosin may lower the risk of developing Parkinson disease.
Behavioral flexibility requires the prefrontal cortex and striatum, but it is unclear if these structures play similar or distinct roles in adapting to novel circumstances. Here, we investigate neuronal ensembles in the medial frontal cortex (MFC) and the dorsomedial striatum (DMS) during one form of behavioral flexibility: learning a new temporal interval. We studied corticostriatal neuronal activity as rodents trained to respond after a 12-second fixed interval (FI12) learned to respond at a shorter 3-second fixed interval (FI3). On FI12 trials, we found that a key form of temporal processing—time-related ramping activity—decreased in the MFC but did not change in the DMS as animals learned to respond at a shorter interval. However, while MFC and DMS ramping was stable with successive days of two-interval performance, temporal decoding by DMS ensembles improved on FI3 trials. Finally, when comparing FI12 vs. FI3 trials we found that more DMS neurons than MFC neurons exhibited differential interval-related activity early in two-interval performance. These data suggest that the MFC and DMS play distinct roles during temporal learning and provide insight into corticostriatal circuits.
Parkinson's disease (PD) causes impaired movement and cognition. PD can involve profound changes in cortical and subcortical brain activity as measured by electroencephalography or intracranial recordings of local field potentials (LFP). Such signals can adaptively guide deep-brain stimulation (DBS) as part of PD therapy. However, adaptive DBS requires the identification of triggers of neuronal activity dependent on real time monitoring and analysis. Current methods do not always identify PD-related signals and can entail delays. We test an alternative approach based on linear predictive coding (LPC), which fits autoregressive (AR) models to time-series data. Parameters of these AR models can be calculated by fast algorithms in real time. We compare LFPs from the striatum in an animal model of PD with dopamine depletion in the absence and presence of the dopamine precursor levodopa, which is used to treat motor symptoms of PD. We show that in dopamine-depleted mice a first order AR model characterized by a single LPC parameter obtained by LFP sampling at 1 kHz for just 1 min can distinguish between levodopa-treated and saline-treated mice and outperform current methods. This suggests that LPC may be useful in online analysis of neuronal signals to guide DBS in real time and could contribute to DBS-based treatment of PD.
There is extensive evidence that glucocorticoid hormones enhance memory consolidation, helping to ensure that emotionally significant events are well remembered. Prior findings suggest that the anteroventral region of bed nuclei of the stria terminalis (avBST) regulates glucocorticoid release, suggesting the potential for avBST activity to influence memory consolidation following an emotionally arousing learning event. To investigate this issue, male Sprague-Dawley rats underwent inhibitory avoidance training and repeated measurement of stress hormones, immediately followed by optogenetic manipulations of either the avBST or its projections to downstream regions, and 48 h later were tested for retention. The results indicate that avBST inhibition augmented posttraining pituitary–adrenal output and enhanced the memory for inhibitory avoidance training. Pretreatment with a glucocorticoid synthesis inhibitor blocked the memory enhancement as well as the potentiated corticosterone response, indicating the dependence of the memory enhancement on glucocorticoid release during the immediate posttraining period. In contrast, posttraining avBST stimulation decreased retention yet had no effect on stress hormonal output. Subsequent experiments revealed that inhibition of avBST input to the paraventricular hypothalamus enhanced stress hormonal output and subsequent retention, whereas stimulation did not affect either. Conversely, stimulation—but not inhibition—of avBST input to the ventrolateral periaqueductal gray impaired consolidation, whereas neither manipulation affected glucocorticoid secretion. These findings indicate that divergent pathways from the avBST are responsible for the mnemonic effects of avBST inhibition versus stimulation and do so via glucocorticoid-dependent and -independent mechanisms, respectively.
Background Terazosin (TZ) and closely related α1‐adrenergic receptor antagonists (doxazosin [DZ] and alfuzosin [AZ]) enhance glycolysis and reduce neurodegeneration in animal models. Observational evidence in humans from several databases supports this finding; however, a recent study has suggested that tamsulosin, the comparator medication, increases the risk of Parkinson's disease. Aims We consider a different comparison group of men taking 5α‐reductase inhibitors (5ARIs) as a new, independent comparison allowing us to both obtain new estimates of the association between TZ/DZ/AZ and Parkinson's disease outcomes and validate tamsulosin as an active comparator. Methods Using the Truven Health Analytics Marketscan database, we identified men without Parkinson's disease, newly started on TZ/DZ/AZ, tamsulosin, or 5ARIs. We followed these matched cohorts to compare the hazard of developing Parkinson's disease. We conducted sensitivity analyses using variable duration of lead‐in to mitigate biases introduced by prodromal disease. Results We found that men taking TZ/DZ/AZ had a lower hazard of Parkinson's disease than men taking tamsulosin (hazard ratio (HR) = 0.71, 95% CI [confidence interval]: 0.65–0.77, n = 239,888) and lower than men taking 5ARIs (HR = 0.84, 95% CI: 0.75–0.94, n = 129,116). We found the TZ/DZ/AZ versus tamsulosin HR to be essentially unchanged with up to 5 years of lead‐in time; however, the TZ/DZ/AZ versus 5ARI effect became attenuated with longer lead‐in durations. Conclusions These data suggest that men using TZ/DZ/AZ have a somewhat lower risk of developing Parkinson's disease than those using tamsulosin and a slightly lower risk than those using 5ARIs. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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